文摘
A practical synthesis of the SGLT-2 inhibitor 尾-C-aryl-an class="smallcaps">dan>-glucoside (1) has been developed. The route employed 2,3,4,6-tetra-O-trimethlysilyl-an class="smallcaps">dan>-glucano-1,5-lactone as the key chiral building block, prepared efficiently from the commercially available, inexpensive raw materials, an class="smallcaps">dan>-gluconolactone and trimethylsilyl chloride. The salient step in the synthesis is the Lewis acid-mediated stereoselective reduction of a methyl C-aryl peracetylated glycoside using a silyl hydride to set the stereochemistry of the crucial anomeric chiral center. Several novel cocrystalline complexes of 1 with an class="smallcaps">lan>-phenylalanine and an class="smallcaps">lan>-proline were discovered. Single-crystal structures of these complexes and several synthetic intermediates have been determined. The an class="smallcaps">lan>-phenylalanine complex was developed and used to purify and isolate the API. All steps were implemented at multikilogram scale.